Breakthrough in Diagnosing Aspirin-Induced Respiratory Disease: The Aspirin Hypersensitivity Diagnostic Index

Aspirin-induced respiratory disease (N-ERD) is a complex and often debilitating condition affecting many individuals who experience severe respiratory reactions to aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). This condition is characterized by chronic rhinosinusitis with nasal polyps, asthma, and a significant reduction in quality of life. However, diagnosing N-ERD has long been challenging due to the lack of reliable biomarkers and the variability in clinical presentations. Recently, a groundbreaking study published in the journal Allergy introduced the Aspirin Hypersensitivity Diagnostic Index (AHDI), a novel in vitro diagnostic tool that promises to revolutionize the diagnosis of N-ERD.

GRAPHICAL ABSTRACT. Fig.1 In vitro test for diagnosing of N-ERD based on urinary 15-oxo-ETE and LTE4 excretion. (Mastalerz L., et al., 2025)

Understanding N-ERD: A Complex Condition

N-ERD is a specific asthma phenotype that manifests through acute respiratory reactions following the ingestion of NSAIDs, including aspirin. This condition is often accompanied by chronic rhinosinusitis with nasal polyps (CRSwNP), making it particularly difficult to manage and treat. The underlying pathophysiology of N-ERD involves the dysregulation of arachidonic acid (AA) metabolism, leading to the overproduction of pro-inflammatory leukotrienes and prostaglandins. One key metabolite, 15-oxo-eicosatetraenoic acid (15-oxo-ETE), has been identified as a potential biomarker for this condition.

The Quest for a Reliable Biomarker

Identifying a reliable biomarker for N-ERD has been a significant challenge for researchers and clinicians. Traditional diagnostic methods, such as oral aspirin provocation tests, are invasive and carry risks of severe reactions. Therefore, there has been a need for a non-invasive, accurate, and easily accessible diagnostic tool. The recent study by Mastalerz et al. (2025) addresses this need by proposing the AHDI, an index based on the measurement of urinary 15-oxo-ETE and leukotriene E4 (LTE4) levels.

The Aspirin Hypersensitivity Diagnostic Index (AHDI)

The AHDI is a composite index that incorporates urinary LTE4-to-15-oxo-ETE ratios, corrected for sex and the severity of chronic rhinosinusitis as measured by the Lund-Mackay score. This index was developed using machine learning algorithms to provide the best distinction between N-ERD patients and those with aspirin-tolerant asthma (ATA). The study involved 64 patients with N-ERD, 59 patients with ATA, and 51 healthy controls. The results showed that the AHDI outperformed single measurements of 15-oxo-ETE or LTE4 alone, with an area under the ROC curve of 0.889, sensitivity of 81.97%, specificity of 87.23%, and accuracy of 86.87%.

Study Design and Methodology

The study was meticulously designed to ensure robust results. Participants underwent comprehensive clinical evaluations, including computed tomography (CT) scans of the paranasal sinuses, spirometry, and measurement of plasma and urinary levels of 15-oxo-ETE and LTE4 using high-performance liquid chromatography and tandem mass spectrometry (HPLC-MS/MS). The technical repeatability and precision of these measurements were validated, ensuring the reliability of the data.

The study revealed several key findings:

Plasma and Urinary 15-oxo-ETE Levels: Plasma 15-oxo-ETE levels were significantly higher in N-ERD patients compared to ATA patients and healthy controls. However, urinary 15-oxo-ETE levels did not show significant differences between the groups. This suggests that plasma 15-oxo-ETE may be a more reliable biomarker for N-ERD.
Urinary LTE4 Levels: Urinary LTE4 levels were significantly higher in N-ERD patients, correlating positively with the Lund-Mackay score, indicating the severity of chronic rhinosinusitis.
Sex-Related Differences: Urinary 15-oxo-ETE levels were found to be higher in women than in men, necessitating sex-based correction in the AHDI formula.
Time-Related Variations: Despite some biological variation over time, the AHDI remained stable and effective in distinguishing N-ERD from ATA.

The Potential of AHDI in Clinical Practice

The AHDI offers several advantages over existing diagnostic methods for N-ERD:

Non-Invasive: The AHDI relies on a single urine sample, making it a non-invasive and patient-friendly diagnostic tool.
High Accuracy: With an accuracy of 86.87%, the AHDI provides a reliable means of diagnosing N-ERD.
Practicality: The index can be easily applied in clinical settings, potentially reducing the need for invasive provocation tests.

Future Directions and Research

While the AHDI represents a significant advancement in the diagnosis of N-ERD, further research is needed to fully understand its clinical utility. Future studies should focus on:

Validation in Larger Cohorts: Confirming the robustness of the AHDI in larger, multicenter studies.
Longitudinal Studies: Investigating the long-term stability and predictive value of the AHDI.
Therapeutic Implications: Exploring how the AHDI can guide personalized treatment strategies for N-ERD patients.

Conclusion

The introduction of the Aspirin Hypersensitivity Diagnostic Index (AHDI) marks a significant milestone in the diagnosis of N-ERD. By leveraging the measurement of urinary 15-oxo-ETE and LTE4, corrected for sex and the severity of chronic rhinosinusitis, the AHDI offers a reliable, non-invasive, and accurate diagnostic tool. This innovation has the potential to transform clinical practice, improve patient outcomes, and enhance the quality of life for individuals suffering from this challenging condition. As research continues to unfold, the AHDI stands as a beacon of hope for better diagnosis and management of N-ERD.

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Reference

Mastalerz, Lucyna, et al. "Aspirin hypersensitivity diagnostic index (AHDI): In vitro test for diagnosing of N‐ERD based on urinary 15‐oxo‐ETE and LTE4 excretion." Allergy 80.2 (2025): 534-544.

This article is for research use only. Do not use in any diagnostic or therapeutic application.